KR102494543B1 - Soluble microneedle patch for delivery of HPV vaccine - Google Patents

Abstract

The present invention relates to a skin administration system for an HPV vaccine capable of exhibiting excellent effects by stably impregnating the HPV vaccine and effectively delivering it into the skin, and is characterized in that it is a microneedle containing an HPV vaccine.

Description

Soluble microneedle patch for delivery of HPV vaccine {Soluble microneedle patch for delivery of HPV vaccine}

The present invention relates to microneedles and microneedle patches.

In general, microneedles are used for delivery of active substances such as drugs in vivo, detection of analytes in the body, and biopsy. The purpose of delivery of pharmaceutically or cosmetically active ingredients using microneedles is to deliver active substances through the skin rather than through a biological circulatory system such as blood vessels or lymphatic vessels.

As a method of using these microneedles, a microneedle device such as a roller to which microneedles are attached is used to form a certain number of holes in the skin and then reapplying drugs, active ingredients on the surface of the microneedles Forms in which the active ingredient is administered simultaneously with skin puncture by coating (active ingredient) are generally used.

Meanwhile, cervical cancer is the second most common cancer in women worldwide, with more than 490,000 new cases occurring annually and more than 270,000 deaths from cervical cancer (Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74-108). In Korea, cervical cancer has the fifth highest incidence in women after breast cancer, stomach cancer, colorectal cancer, and thyroid cancer, accounting for 9.8% of all female cancers (Chung HH et al., Cervical cancer incidence and survival in Korea: 1993 -2002. Int J Gynecol Cancer 2006;16: 1833-1838). The introduction of cervical cancer cytology (Pap smear) has contributed greatly to lowering the incidence and mortality of cervical cancer, but there are also problems with high false negative rates and consequent increase in costs.

Human papillomavirus (HPV) infection is the most important risk factor for cervical cancer, and HPV DNA can be found in more than 99% of cervical cancer. Since HPV is mainly transmitted through sexual contact, continuous use of contraceptives such as condoms can reduce the risk of infection by about 70%, but it is not perfect. Accordingly, an HPV vaccine was developed to prevent cervical cancer, and as the HPV vaccine was approved in 2006, an increasing number of countries are implementing HPV vaccine as a national vaccination program.

In general, HPV (Human papillomavirus) vaccines were inoculated by intramuscular injection three times over a period of six months. Therefore, there is a problem that the inoculated person may be afraid of the injection and may avoid it, and pain and side effects may occur when the inoculator's skill is low.

Therefore, there is a need for a new method that can be effectively used for HPV vaccination without side effects.

Republic of Korea Patent Publication No. 10-2014-0125364

An object to be solved by the present invention is to provide a system for stably impregnating a soluble microneedle with an HPV vaccine and effectively delivering the HPV vaccine into the skin, and a method for manufacturing such a system.

Accordingly, the present invention provides soluble microneedles comprising an HPV vaccine.

In addition, the present invention provides a microneedle patch including the microneedles.

In addition, the present invention provides a method for preparing a microneedle containing an HPV vaccine.

In order to solve the above problems, the present invention provides soluble microneedles containing an HPV vaccine, and more preferably, the material forming the microneedles is dissolved in the skin, so that when the microneedles are applied to the skin, the microneedles dissolve or Disruption releases the HPV vaccine into the skin.

After a long period of research, the present inventors impregnated the HPV vaccine into soluble microneedles to effectively deliver the HPV vaccine into the skin, increase efficiency by supplying the vaccine to dendrite cells, and have excellent HPV preventive effects, as well as conventional injections. In the case of inoculation, it was confirmed that there is no concern about pain and / or side effects caused by the injection needle, and the present invention was completed.

As used herein, the term "HPV vaccine" includes both approved and non-approved HPV vaccines, including, for example, Gardasil (Merck), Cervarix (GlaxoSmithKline), etc. can do.

The present inventors have studied various administration systems and none of the systems are similar to the method of impregnating the soluble microneedles of the HPV vaccine. After many efforts, the present inventors made a surprising invention that confirmed a remarkable effect without side effects by impregnating microneedles with HPV vaccine. In addition, by using the microneedle according to the present invention, an HPV vaccine can be easily inoculated without side effects by an unskilled ordinary person in a non-invasive manner, and since all vaccines can be delivered intradermally, excellent effects can be exhibited.

As used herein, the term "impregnation" may refer to a form in which the HPV vaccine can be contained in the microneedles, and preferably i) contains the HPV vaccine together with the soluble material forming the microneedles (microneedle structure HPV vaccine may be dispersed within), or ii) microneedles may be pierced and the HPV vaccine may be contained in the hole. When the microneedles are prepared in the form of i) or ii), the HPV vaccine can effectively penetrate into the skin, and it is preferable to prepare the microneedles in the form of i).

Therefore, it is most preferable that the substance forming the microneedles is dissolved in vivo so that the HPV vaccine contained in the microneedles is effectively released into the skin.

In a preferred embodiment of the present invention, the material forming the microneedles is dissolved in the skin, so that the microneedles dissolve or collapse when the microneedles are applied to the skin, so that the HPV vaccine contained in the microneedles can effectively penetrate into the skin. can

In the present invention, the microneedles may preferably be soluble in the skin, and to form soluble microneedles, for example, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose) , water-soluble polymers such as vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, and polyvinylpyrrolidone; sugars such as xylose, sucrose, maltose, lactose, and trehalose; or mixtures thereof may be used. In particular, considering the skin penetration strength of the microneedle and the dissolution rate in the skin comprehensively, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), and saccharide (preferably is preferably a mixture of trehalose), more preferably a mixture of glycerin.

Preferably, the microneedles of the present invention may additionally include a plasticizer, a surfactant, a preservative, an anti-inflammatory agent, and the like in addition to the above components forming the microneedles.

As the plasticizer, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin are used alone. or may be used in combination.

Although the length of the microneedles according to the present invention is not limited to a specific size, it is preferable to apply them within a range that does not come into contact with nerves and blood vessels because pain and drug delivery efficiency may be affected when the microneedles are applied. . Therefore, the length of the microneedle according to the present invention is not limited thereto, but may preferably be about 200 to 500 μm.

In the present invention, the HPV vaccine may be included in 0.00001 to 1% by weight, preferably 0.0001 to 0.5% by weight, based on the weight of the preparation solution for preparing microneedles, based on the total weight of the preparation solution. 0.001 to 0.1% by weight may be included. When included in less than 0.00001% by weight, effective effects may not be exerted, and when included in more than 1% by weight, physical properties and durability of microneedles may be affected, which is undesirable.

In the present invention, the HPV vaccine may be included in 0.00001 to 4% by weight, preferably 0.0001 to 2% by weight, more preferably 0.001 to 0.4% by weight, based on the total weight of the microneedles. When included in less than 0.00001% by weight, an effective effect may not be exhibited, and when included in more than 4% by weight, physical properties and durability of microneedles may be affected, which is undesirable.

When the microneedle according to the present invention is applied to the skin, the amount of skin penetration can be remarkably improved compared to other conventional skin administration systems.

In addition, the present invention provides a microneedle patch including the microneedles, that is, a microneedle patch for HPV vaccine administration (or delivery) to which the microneedles are attached.

In the present invention, the patch may mean a sheet to which one or more microneedles impregnated with the HPV vaccine of the present invention are attached and the surface to which the microneedles are attached can be attached to the skin. The size of the sheet is not limited to a specific size, and may be appropriately adjusted according to the amount of HPV vaccine to be absorbed into the skin or the attachment site. In addition, one or more, preferably a plurality of microneedles may be attached to the surface of the sheet attachable to the skin.

In addition, the surface of the patch that can be attached to the skin can also contain the HPV vaccine so that the HPV vaccine can penetrate the hole formed by the microneedles, and the HPV vaccine is impregnated into the microneedles to achieve an excellent skin administration effect. It is desirable to do

In addition, the present invention comprises the steps of S1) filling and mixing a material for forming microneedles including an HPV vaccine and a material soluble in the skin in a mold; and S2) warming and drying the mold and then separating the mold.

The method can be prepared by impregnating the HPV vaccine into microneedles, and the impregnation is preferably, but not limited to, i) containing the HPV vaccine together with soluble substances in the skin forming microneedles, or ii) microneedles. piercing a needle and containing the HPV vaccine within the puncture; and the like.

In the present invention, in order to impregnate the HPV vaccine into the microneedles, the material forming the structure of the microneedles and the HPV vaccine are mixed together in a mold for forming the microneedles, and then the mold is heated, dried, and separated to obtain microneedles. Needles can be made.

In the present invention, the soluble substance in the skin is, for example, hyaluronic acid (Hyaluronic acid), sodium carboxymethyl cellulose (Na-CMC, sodium carboxymethyl cellulose), vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (Poly vinyl alcohol), and water-soluble polymers such as polyvinylpyrrolidone (Poly vinyl pyrrolidone); sugars such as xylose, sucrose, maltose, lactose, and trehalose; or mixtures thereof may be used.

By using the microneedle according to the present invention, HPV vaccine can be easily inoculated without side effects by an unskilled general public in a non-invasive way, and since all vaccines can be delivered intradermally, the efficiency is increased and the effect is equal to or higher than that of intradermal inoculation. can pay In addition, the vaccine contained in the soluble microneedles has an advantage in that it has a sustained release form, thereby increasing efficiency and reducing the number of inoculations.

The following drawings attached to this specification illustrate preferred embodiments of the present invention, and serve to further understand the technical idea of the present invention together with the contents of the above-described invention, so the present invention is limited to those described in the drawings. should not be construed as limiting.
1 is a view showing one example of several methods for manufacturing microneedles according to the present invention.
2 is a diagram showing a Franz diffusion cell for evaluating drug release behavior of microneedles according to the present invention.
3 is a graph showing the skin permeation amount of Gardasil of Example 1.

Hereinafter, examples and the like will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

<Preparation of soluble microneedles>

Soluble microneedles are prepared by a solution casting method, and the solution is cast into a mold, filled with a liquid in a micromold by vacuum or centrifugal separation, and then dried.

As the material forming the microneedle structure, general synthetic and natural water-soluble polymers were used.

<Preparation of soluble microneedles containing HPV vaccine (Example 1)>

ingredient Example 1
(Unit: % by weight) oligo-HA 6 Na-CMC 6 Trehalose 8 Glycerin 5 HCO-40 0.2 HPV vaccine
(Gardasil) 10 water To 100

After dissolving Oligo-HA (Hyaluronic acid), Na-CMC (Sodium carboxymethyl cellulose) and Trehalose in purified water, glycerin, PEG-40 hydrogenated castor oil (HCO-40) and HPV vaccine Gardasil (Gardasil) was added to prepare a microneedle solution. The prepared solution was cast in a silicon microneedle mold, and then centrifuged at 3000 rpm for 10 minutes to fill the micromold with the liquid. After filling the solution, it was dried in a drying oven (70° C.) for 3 hours, and the microneedles were separated from the silicon mold using an adhesive film (Example 1).

(The content of the HPV vaccine in the Gardasil is 0.0024% by weight, and as an example, the water in the preparation solution may be 75% by weight, and in this case, the content of the HPV vaccine after drying is 0.0096% by weight)

< Experimental example 1>

drug release behavior

The present inventors measured the Gardasil vaccine content of the acceptor solution over time using a Franz diffusion cell using liquid chromatography.

To this end, Gardasil-impregnated microneedles (Example 1) were attached to pig skin and the skin permeation amount of the Gardasil vaccine over time was compared.

As a result, as shown in FIG. 3, it was confirmed that the porcine skin penetrated with the Gardasil vaccine by the Gardasil-containing microneedles was gradually released over time. It was confirmed that this has the effect of reducing the number of vaccinations due to a longer stay in the body compared to conventional injections.

Claims (8)

A water-soluble microneedle for skin penetration containing a material forming a microneedle and a human papillomavirus (HPV) vaccine,
The material forming the microneedle may be hyaluronic acid or a salt thereof; carboxymethyl cellulose or a salt thereof; trehalose; and glycerin,
Water-soluble microneedle, characterized in that when the microneedle is applied to the skin, the material forming the microneedle is dissolved by moisture in the skin. delete delete delete According to claim 1,
The water-soluble microneedle, characterized in that the HPV vaccine contains 0.00001 to 4% by weight relative to the total weight of the microneedle. According to claim 1,
The microneedle is a water-soluble microneedle, characterized in that to improve the skin penetration of the HPV vaccine. A microneedle patch comprising the water-soluble microneedle according to any one of claims 1, 5 and 6. A method for manufacturing a water-soluble microneedle according to claim 1,
S1) filling and mixing the HPV vaccine and the material for forming the microneedle in a mold; and
S2) The method of manufacturing a water-soluble microneedle comprising the step of heating and drying the mold and then separating the mold.

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